A Japanese study finds that the addition of oxaliplatin (Eloxatin, Sanofi-Aventis) to fluoropyrimidine with bevacizumab, does not extend progression-free survival in elderly patients with metastatic colorectal cancer and in fact, can lead to more severe adverse events.
The results of the trial were presented by Tetsuya Hamaguchi, MD, PhD, at the 2022 Gastrointestinal Cancers Symposium.
Fluoropyrimidine with oxaliplatin and bevacizumab is a standard intensive initial therapy for metastatic colorectal cancer, but how well this combination works in elderly patients isn’t known because few clinical trials include senior-aged patients. It is known that the combination of fluoropyrimidine and bevacizumab can lead to significantly longer progression-free survival in elderly patients with metastatic colorectal cancer.
Dr. Hamaguchi, an oncologist with Saitama Medical University International Medical Center in Hidaka, Japan, included 251 patients (93% were at least 75 years old) with newly diagnosed metastatic colorectal cancer in a randomized, phase 3 trial of modified FOLFOX7 (folinic acid, fluorouracil, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) plus bevacizumab versus 5-fluorouracil/l-LV or capecitabine plus bevacizumab.
The patients were treated between September 2012 and March 2019. 125 patients received combination therapy and 126 received the addition of oxaliplatin. Researchers found the addition of oxaliplatin to fluoropyrimidine with bevacizumab did not extend progression-free survival and it was associated with more frequent and severe adverse events, including neutropenia, nausea, stomatitis, diarrhea, fatigue, sensory neuropathy, and hypertension.
Triggering sensory neuropathy
At issue is neuropathy caused by oxaliplatin. Grade 3 neuropathy can occur in 25% of patients after 12 cycles of FOLFOX. It has also been recorded in more than 20% of patients at 18 months, according to Gabriel Brooks, MD, an oncologist with the Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, N.H., who served as the discussant for the oral abstract session featuring the study presented by Dr. Hamaguchi.
“Even if we carefully ask our patients about their symptoms, and even if we stop oxaliplatin as soon as they have evidence of grade 2 neuropathy, many of those patients who didn’t have any neuropathy when the oxaliplatin is stopped will go on to develop it. And many of those patients who have grade 2 neuropathy will have worsening of their neuropathy and it will become a grade 3 neuropathy, even if we try to stop conscientiously,” Dr. Brooks said during his presentation.
The MOSAIC trial demonstrated that oxaliplatin improved disease-free and overall survival when added to 5-fluorouracil in the adjuvant treatment of stage II/III colon cancer. However, neuropathy concerns led to studies examining shortened regimens in an effort to reduce neuropathy incidence. In 2018, the IDEA study compared 3 months versus 6 months of oxaliplatin with fluoropyrimidine as adjuvant therapy for stage III colon cancer. The study found that the 6-month regimen was superior with respect to disease-free survival, but the benefit was very small, according to Dr. Brooks.
“What was not small was the difference in the incidence of [grade] 3-4 neuropathy, which was only 2.5% among patients who received 3 months of adjuvant chemotherapy with oxaliplatin, and it was 15.9% among people randomized to 6 months of adjuvant chemotherapy,” he said. The same study suggested that 3 months of the CapeOX regimen is noninferior to 6 months.
The new study included patients aged 70-74 years with Performance Status 2, or 75 or older with PS 0-2. They were randomized to receive fluoropyrimidine plus bevacizumab (arm A) or fluoropyrimidine, bevacizumab, and oxaliplatin (arm B). The study had to be terminated because of poor accrual, and the study was later amended to include a smaller required sample size. After a recruitment of 251 patients and a 2-year minimum follow-up, there was no significant difference in progression-free survival between the two groups (hazard ratio, 0.837; one-sided P = .086), overall survival, or objective response rate.
Adverse events were more common in the oxaliplatin group, including neutropenia (24% vs. 15%), nausea (22% vs. 10%), diarrhea (16% vs. 7%), fatigue (32% vs. 21%), and sensory neuropathy (57% vs. 15%).
Subgroup analyses did identify a subgroup of patients with KRAS wild type benefited from oxaliplatin (HR, 0.578; 95% confidence interval, 0.380-0.879), and Dr. Brooks said that this echoes findings from other studies.
Dr. Brooks advocated for deintensification of oxaliplatin. “The benefits of oxaliplatin are less than are often assumed in multiple settings, and the harms of oxaliplatin are well described. We are probably overly aggressive in our use of oxaliplatin. I submit that we should use oxaliplatin cautiously and sparingly in a couple of situations: We should use it very cautiously and sparingly beyond the third month of adjuvant therapy for colon cancer, and we should use it cautiously and sparingly in elderly or frail patients with metastatic colorectal cancer.”
The study was funded, in part, by the National Cancer Center Research and Development Fund, Grant-in-Aid for Clinical Cancer Research, and the Agency for Medical Research and Development in Japan. Dr. Brooks has consulted for CareCentrix, Ipsen, and UnitedHealthcare and has received research funding from Boston Biomedical and Roche/Genentech. Dr. Hamaguchi has received honoraria from Bayer, Bristol-Myers Squibb Japan, and other pharmaceutical companies. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.